Molecular Genetic Classification of Central Nervous System Malformations

Abstract

Traditional schemes of classifying nervous system malformations are based on descriptive morphogenesis of anatomic processes of ontogenesis, such as neurulation, neuroblast migration, and axonal pathfinding. This proposal is a first attempt to incorporate the recent molecular genetic data that explain programming of development etiologically. A scheme based purely on genetic mutations would not be practical, in part because only in a few dysgeneses are the specific defects known, but also because several genes might be involved sequentially and many genes inhibit or augment the expression of others. The same genes serve different functions at different stages and are involved in multiple organ systems. Some complex malformations, such as holoprosencephaly, result from several unrelated defective genes. Finally, a pure genetic classification would be too inflexible to incorporate some anatomic criteria. The basis for the proposed scheme is, therefore, disturbances in patterns of genetic expression; polarity gradients of the axes of the neural tube (eg, upregulation or downregulation of genetic influences); segmentation (eg, deletions of specific neuromeres, ectopic expression); mutations that cause change in cell lineage (eg, dysplastic gangliocytoma of cerebellum, myofiber differentiation within brain); and specific genes or molecules that mediate neuroblast migration in its early (eg, filamin-1), middle (eg, LIS1, double-cortin), or late course (eg, reelin, L1-CAM). The proposed scheme undoubtedly will undergo many future revisions, but it provides a starting point using currently available data.

Trigeminal nerve agenesis with absence of foramina rotunda in Gómez–López–Hernández syndrome

“…While multiple mechanisms have been proposed, the etiology of RS remains unclear and there have been no specific chromosomal abnormalities identified to date [Utsunomiya et al, 1998;Sarnat, 2000;Yachnis 2002;Pasquier et al, 2009;Ishak et al, 2012;de Mattos et al, 2014;Whitehead et al, 2014]. It is important to note that RS has been associated with syndromes other than GLHS, including holoprosencephaly and VACTERL association Tully et al, 2012;Weaver et al, 2013;Abdel-Salam et al, 2014].…”

Sequence of Synaptogenesis in the Fetal and Neonatal Cerebellar System - Part 1: Guillain-Mollaret Triangle (Dentato-Rubro-Olivo-Cerebellar Circuit)

“…These axes and gradients of genetic expression are a fundamental principle of neuroembryology and explain not only the normal progression of maturation but also can explain many malformations [46,47,48]. In the context of embryonic hindbrain segmentation, inferior olivary nucleus is formed in rhombomeres 6 and 7, whereas the dentate and other deep cerebellar nuclei develop from rhombomere 2.…”

The Cerebellum in Chiari Type II Malformation

“…Chiari proposed through his publications in the 1890s that occipital bone abnormalities might be responsible for these malformations [12] . The molecular genetic theory proposes a disturbance of rhombomeric segmentation and ectopic expression in the embryonic hindbrain due to genetic mutation [21] . Sarnat [22] found that ependymal vimentin was overexpressed only in areas of dysgenesis in fetuses and young infants with CII.…”

“…However, this view is not held universally [21,22] . The cerebellar vermis lobules, flocculi, tonsils, superior, and inferior medullary veli are not aplastic and can be identified on MRI scans in children with CII [31] .…”